alexa Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T cells to Sulphamethoxazole-Hydroxylamine Induced Toxicity | OMICS International | Abstract
ISSN: 2572-0805

HIV: Current Research
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Research Article

Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T cells to Sulphamethoxazole-Hydroxylamine Induced Toxicity

Kemi Adeyanju1,2, Gregory A. Dekaban1,2* and Michael J. Rieder1,3

1Biotherapeutics Research Laboratory, Molecular Medicine, Robarts Research Institute, London, Ontario, Canada

2Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada

3Department of Pediatrics and Physiology & Pharmacology, Schulich School of Medicine & Dentistry,University of Western Ontario, London, Ontario, Canada

*Corresponding Author:
Dekaban GA
Scientist, BioTherapeutics Research Laboratory Director, Molecular Medicine
Robarts Research Institute, Professor, Department of Microbiology and Immunology
University of Western Ontario, 1151 Richmond Street North London, Ontario, Canada
Tel: + 519-931-5777
E-mail: [email protected]

Received date: May 25, 2016; Accepted date: June 13, 2016; Published date: June 20, 2016

Citation: Adeyanju K, Dekaban GA, Rieder MJ (2016) Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T cells to Sulphamethoxazole-Hydroxylamine Induced Toxicity. HIV Curr Res 1:105. doi: 10.4172/2572-0805.1000105

Copyright: © 2016 Adeyanju K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: One medication commonly used by HIV-1-infected individuals is the antimicrobial sulphamethoxazole (SMX), which is used in the treatment and prophylaxis of pneumocystis pneumonia. However, SMX is responsible for a very high incidence of hypersensitivity adverse drug reactions (ADRs) in the HIV-1 population. While the pathophysiology of ADRs in general is unknown, sulphamethoxazole-mediated ADRs have been linked to its reactive metabolite sulphamethoxazole-hydroxylamine (SMX-HA). Our previous work has shown that increased expression of the HIV-1 Tat protein in T cells correlated with increased apoptosis after incubation with SMX-HA. In this study we sought to determine the region of the Tat protein responsible for this effect and the mechanism by which Tat contributed to SMX-HA mediated apoptosis.
Methods: We established Jurkat T and Cos 7 cell lines that stably expressed full-length Tat (Tat101) and deletion mutants (Tat86, Tat72, Tat48 and TatΔ). These cell lines were then incubated with SMX-HA and assayed for cell viability and production of reactive oxygen species (ROS). We further used confocal microscopy to assess the intracellular distribution of the Tat proteins and to determine if changes in the expression and/or localization of key cytoskeleton proteins contributed to Tat-mediated apoptosis after SMX-HA treatment.
Results: Deletion of regions of Tat that lead to increased cytoplasmic accumulation significantly contributed to increased cell death in the presence of SMX-HA. The increased cell death did not require induction of ROS. Quantitative analysis also showed that the Tat-expressing cell lines had significantly lower levels of β-actin and α-tubulin present both before and after treatment with SMX-HA. Increased cytoplasmic localization of Tat correlated with greater disturbances in the distribution of actin filaments.
Conclusion: The presence of cytoplasmic Tat in T and epithelial cell lines increases their sensitivity to SMX-HA induced cell death, an effect mediated by the first 48 amino acids of TAT.

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